Method of treating xerostomia

ABSTRACT

An oral care compositon is described for use in the treatment or alleviation of the symptoms of dry mouth comprising polyvinyl pyrrolidone (PVP) or a derivative thereof, an anionic mucoadhesive polymer and an orally acceptable carrier or excipient.

CROSS REFERENCE TO PRIOR APPLICATIONS

This application is a divisional of U.S. application Ser. No. 11/572,751filed Aug. 15, 2008 which is a 371 of PCT/EP2005/008327 filed Jul. 29,2005 which claims the priority of GB 0502077.1 filed Feb. 1, 2005 and GB0417193.0 filed Aug. 2, 2004.

The present invention relates to mucoadhesive agent-containingcompositions for oral use, such as toothpastes, sprays, mouthwashes,gels, lozenges, chewing gums, tablets, pastilles, instant powders, oralstrips and buccal patches etc, and to the use of such compositions as anoral lubricant and to alleviate the discomfort associated withxerostomia.

Xerostomia, or dry mouth, is a condition in which an excessive drynesswithin the oral cavity occurs. Xerostomia is not itself a disease, but asymptom of various medical conditions, a side effect of radiation to thehead and neck, or a side effect of a variety of medications. Xerostomiais a common complaint found often among older adults; however, does notappear to be related to age itself.

Xerostomia is often a contributing factor for both minor and serioushealth problems; it can affect nutrition and dental, as well aspsychological health. Some common problems associated with xerostomiainclude a constant sore throat, burning sensations, difficulty speakingand swallowing, hoarseness and/or dry nasal passages. If left untreated,xerostomia decreases the oral pH and significantly increases thedevelopment of plaque and dental caries. Oral candidosis is one of themost common oral infections seen in association with xerostomia.

In view of the above, it would be advantageous to provide compositionsfor oral use as a lubricant to alleviate the discomfort associated withxerostomia.

U.S. Pat. No. 5,496,558, aims to address these problems with theprovision of solid-form xerostomia products in the form of a lozenge,tablet, chewing gum and pastille, comprising a lubricating polymer,polyethylene glycol, an organic acid and sorbitol. U.S. Pat. No.5,612,207 aims to address these problems with the provision of a lozengecomprising a hard candy base, a demulcent, a humectant and an organicacidulant.

However, there remains a need for alternative formulations with goodmouth feel; that are able to lubricate and hydrate the mouth.

It has been found that the symptoms of dry mouth may be reduced by theuse of an oral care composition comprising a combination of polyvinylpyrrolidone (PVP) or a derivative thereof with an anionic mucoadhesivepolymer.

A mucoadhesive polymer of the invention has an affinity for biologicalsurfaces especially towards mucous membranes of the oral cavity.Mucoadhesive agents as used in the invention may be natural orsynthetic.

Accordingly, the present invention provides a composition comprising PVPor a derivative thereof, an anionic mucoadhesive polymer and an orallyacceptable carrier or excipient.

The compositions according to the present invention have good mouthcoating, lubrication and mouth feel properties. Whilst compositionscomprising an anionic mucoadhesive polymer are able to provide a goodcoating, they can suffer from negative sensory properties of being tootacky in use. This negative sensory property has surprisingly beenovercome by the addition of PVP or a derivative thereof to an anionicmucoadhesive polymer.

Suitable derivatives of PVP include a vinyl pyrrolidone/vinyl acetate(VPNA) copolymer or a vinyl pyrrolidone/vinyl alcohol (VPNOH) copolymer.Preferably, compositions of the present invention comprise PVP or VPNAcopolymer

Compositions of the present invention may suitably comprise from 0.1 to20% w/w of PVP or a derivative thereof, preferably from, 0.5 to 10% w/wand more preferably 0.6 to 8% w/w.

The anionic mucoadhesive polymers useful in the present invention may bea cellulose gum, a saccharide gum or a polyacrylic acid polymer, or amixture thereof.

Suitable cellulose gums include a carboxymethylcellulose (CMC) gum, forexample sodium carboxymethylcellulose.

Suitable saccharide gums for use in the present invention includexanthan gum, guar gum, gum Arabic, tragacanth, gum karaya, locust beangum and pectin or a mixture thereof. Xanthan gum is preferred.

Suitable polyacrylic acid polymers include carbomers, acrylate/C₁₀₋₃₀alkyl acrylate cross polymers or polycarbophils available from NoveonInc, 9911 Brecksville Road, Cleveland, Ohio 44141-3247. Preferredpolyacrylic acids are carbomers or acrylate/C₁₀₋₃₀ alkyl acrylate crosspolymers.

Suitably compositions of the present invention may comprise acombination of sodium carboxymethylcellulose and xanthan gum.

Suitably compositions of the present invention may comprise from 0.02 to20% w/w of the anionic mucoadhesive polymer, preferably from 0.1 to 10%w/w, more preferably from 0.15 to 4% w/w, and most preferably from 0.2to 2% w/w.

Suitably the compositions of the present invention may comprise PVP or aderivative thereof and an anionic mucoadhesive polymer in a weight ratioof from 5:1 to 1:1, preferably from 4:1 to 2:1.

Compositions of the present invention may further comprise a siliconbased oil, such as dimethicone or simethicone in an an amount up to 8%w/w, eg from 1 to 5% w/w. The hydrophobic nature of the silicon basedoil enhances the lubricity of the compositions in the oral cavity.

The oral compositions of the present invention are typically formulatedin the form of toothpastes, sprays, mouthwashes, gels, lozenges(including centre filled lozenges), chewing gums, tablets, pastilles,instant powders, oral strips and buccal patches etc. Preferredcompositions of the present invention are mouth sprays, mouthwashes andoral gels.

Known oral strips or buccal patches can be adapted to deliver thecombination of polymers of the present invention to the oral cavity. Forexample a multilayered erodible film as disclosed in WO 03/015748 and US04/0062724 may incorporate PVP or a derivative thereof and an anionicmucoadhesive polymer of the present invention either in the adhesivefirst layer and/or the erodible second layer as disclosed therein. Ifdesired a silicon based oil can be used alone or with other hydrophobicpolymers to be incorporated into or to coat the erodible layer asdisclosed therein.

Suitable orally acceptable carriers and excipients include abrasivepolishing materials (especially for a dentifrice), flavouring agents,humectants, binders, sweetening agents, surfactants, preservatives,buffering agents, colouring agents and water.

Suitable humectants for use in compositions of the invention includeglycerine, sorbitol, xylitol, propylene glycol or polyethylene glycol,or mixtures thereof; which humectant may be present in the range from 5to 70%.

Suitable flavouring agents for use in the present invention includepeppermint, spearmint, and fruit flavours. Flavouring agents provide anadditional benefit in stimulating salivary flow, which helps alleviatethe symptoms of dry mouth. If desired, additional salivary stimulantscan be included such as edible organic acids, e.g. citric acid.

Suitable preservatives for use in the invention include parabens (methyland propyl parabens), sodium benzoate, and potassium sorbate.

Suitable buffering agents for use in the invention include phosphatebuffers such as disodium phosphate, sodium phosphate or citrate buffers.

Suitable surfactants for use in the invention includepolyethyleneglycols (PEG), hydrogenated caster oils, sorbitan esters,polyethylene-polypropylene tri-block copolymers (such as Poloxamers™).Preferred surfactants include PEG-40 or PEG-60 hydrogenated castor oiland sorbitan esters.

Additional ingredients suitable for use in the invention includeremineralising agents, antimicrobial agents, anti-caries agents,anticalculus agents, moisturising agents, breath freshening agents anddesensitising agents.

Suitable antimicrobial agents for use in the invention includechlorhexidine, cetylpyridinium chloride, zinc salts or triclosan.Preferred antimicrobial agents are cetylpyridinium chloride,chlorhexidine and zinc salts.

Suitable anti-caries agents for use in the invention include a source offluoride ions such as an alkali metal salt, for example sodium fluoride,or sodium monofluorophosphate, tin (II) fluoride or an amine fluoridesalt such as Olaflur or Decaflur. Suitably the composition will comprisebetween 1 and 2500 ppm of fluoride ions.

Compositions according to the present invention may be prepared byadmixing the ingredients in the appropriate relative amounts in anyorder that is convenient and thereafter and if necessary including abuffering agent to adjust the pH to give the final desired value.

The compositions according to the present invention will have a pH whichis orally acceptable, typically ranging from about pH 5 to 10 and morepreferable pH 5.5 to 8.

Mouthwash and mouth spray compositions may be provided in a “ready touse” form; as a concentrated solution, for dilution by the userimmediately prior to use; or in solid form, such as a tablet or asinstant powder in a sachet, for dissolution by the user immediatelyprior to use. Tablets may suitably be prepared using xylitol and/orsorbitol as the major ingredient. The sachets and tablets may beformulated to provide, on dissolution, a still mouthwash, or, by theincorporation of a suitable effervescent couple, for instance sodiumcarbonate/bicarbonate and citric acid, an effervescent mouthwash.

The compositions of the present invention are of use in alleviating thesymptoms of xerostomia. In particular they are of use in lubricating andhydrating the oral cavity.

The present invention also provides a method for treating xerostomia ina human or animal, wherein said method comprises administration of atherapeutically effective amount of a composition as hereinbeforedescribed.

The present invention is illustrated by the following examples but isnot limited thereby.

EXAMPLE 1—MOUTHSPRAY 1

Ingredient Amount % w/w Water 52.940 Glycerin 35.000 Xylitol 7.500 VP/VAcopolymer 1.000 PEG 60 Hydrogenated castor oil 1.600 Flavour ingredients0.810 Sodium benzoate 0.500 Xanthan gum 0.400 Methylparaben 0.100Propylparaben 0.100 Cetylpyridinium chloride 0.050

EXAMPLE 2—MOUTH SPRAY 2

Ingredient Amount % w/w Water 51.750 Glycerin 35.000 Xylitol 7.500 PVP2.640 PEG 60 Hydrogenated castor oil 0.850 Flavour ingredients 0.810Sodium benzoate 0.500 Xanthan gum 0.400 Cellulose gum 0.400 AloeBarbadensis 0.100 Cetylpyridinium chloride 0.050

EXAMPLE 3—MOUTHWASH

Ingredient Amount % w/w Water 84.214 Glycerin 7.000 Sorbitol 5.000Poloxamer 338 1.000 PEG 60 Hydrogenated castor oil 1.000 VP/VA copolymer0.750 Sodium benzoate 0.500 Cellulose gum 0.200 Flavour ingredients0.120 Cetylpyridinium chloride 0.050 Methyl paraben 0.050 Propyl paraben0.050 Sodium saccharin 0.050 Xanthan gum 0.010 Disodium phosphate 0.003Sodium phosphate 0.002 FD&C Blue No. 1 0.001

EXAMPLE 4—ORAL GEL

Ingredient Amount % w/w PVP 8.000 Cellulose 1.000 Carbomer 1.000Sorbitol 25.000 Xylitol 10.000 Glycerin 19.000 Flavour ingredients 0.100FD&C Blue No. 1 (1% solution) 0.400 Water 35.500

EXAMPLE 5—SENSORY EVALUATION

Sensory evaluation for the optimisation of polymers for use inxerostomia applications was performed using small scale panel testing.Sensory findings include:

The use of CMC alone at a level which provides good mouth coatingproduced sensory negatives of ‘tacky’ and ‘gloopy’.

Sensory testing of Xanthan gum alone, at levels which provided goodmouth coating, produced negative sensory feedback of ‘gloopy’ andcomments of tackiness

A blend of CMC, Xanthan gum and PVP was found to deliver good coatingwith a smooth, good mouthfeel and the ability to lubricate and hydratethe mouth. This polymer combination was tested alongside a CMC, Xanthan,Dimethicone combination. Substitution of the PVP for Dimethicone reducedthe coating benefit and smoothness of the polymer blend.

The sensory negatives associated with the use of CMC or Xanthan alone,which deliver coating and mucoadhesion benefits, have been overcome bythe incorporation of PVP in a combination of CMC and xanthan gum, thiseffect is further suggested by the loss of smoothness when PVP wassubstituted in the blend for an alternative polymer resulting in theloss of all smooth type comments.

EXAMPLE 6—SENSORY EVALUATION

Further sensory evaluation for the optimisation of polymers for use inxerostomia applications was performed using small scale panel testconsisting of six panelists.

Panellists tested 10 ml of polymer solutions as shown in the tablebelow:

Polymer Solution CMC % w/w Xanthan % w/w PVP % w/w Xanthan 1.0 Xanthan +PVP 1.0 2.5 CMC 1.0 CMC + PVP 1.0 2.5 Xanthan + CMC 0.75 0.25 Xanthan +CMC + PVP 0.75 0.25 2.5

Sensory findings include:

CMC/CMC+PVP Solutions

Addition of PVP to a CMC solution improved the organolepticcharacteristics of the polymer solutions. PVP significantly (p=0.01)reduced the tackiness of the CMC solution and provided a smoother oraltexture. The mouthfeel and aftertaste of the CMC+PVP solution was morepleasant. The mouth was more moisturised. Both polymer solutions wereperceived to be moderately gloopy. There was a trend for the CMC+PVPsolution to be perceived as being more viscous and gel like (moregloopy) than the CMC solution. This is explained by the fact that thereis more overall polymer increasing the viscosity of the solution.

Xanthan/Xanthan+PVP

In this small scale panel testing no significant difference was observedbetween the organoleptic characteristics of a xanthan solution and amixture of xanthan and PVP. There was a trend that the addition of PVPto xanthan solution slightly reduced the pleasantness of the mouth feeland the smoothness of the oral texture of the solution owing to anincreased gloopy sensation, which can be explained by the increase inoverall polymer in the system. However, adding PVP increased the abilityto coat the mouth. Both polymers solutions were perceived leaving themouth moderately moisturised and lubricated. Importantly the addition ofPVP reduced the tackiness of the xanthan solution.

Xanthan+CMC/Xanthan+CMC+PVP

Addition of PVP to a xanthan+CMC solution improved significantly(p=0.03) the smoothness of the oral texture of the solution. There was atrend for PVP to reduce tackiness of the xanthan+CMC solution and toprovide a more pleasant mouthfeel and to leave the mouth moisturised andlubricated. Xanthan+CMC+PVP solution was perceived to be more gloopy inview of the fact that there was more overall polymer increasing theviscosity of the solution.

The invention claimed is:
 1. A method of treating xerostomia or mouthdryness by administering to a person in need thereof a liquidcomposition comprising: (A) ingredients in effective amounts fortreating xerostomia or mouth dryness consisting of: (i) polyvinylpyrrolidone or a derivative thereof and (ii) an anionic mucoadhesivepolymer; and (B) one or more orally acceptable carriers or excipientsselected from the group consisting of: flavoring agents, humectants,binders, sweetening agents, surfactants, preservatives, bufferingagents, coloring agents and water.
 2. The method of claim 1, wherein theingredients in effective amounts for treating xerostomia or mouthdryness consist of: (i) polyvinyl pyrrolidone or a derivative thereofand (ii) an anionic mucoadhesive polymer selected from carboxymethylcellulose, xanthan gum, and mixtures thereof.
 3. The method of claim 1,wherein the ingredients in effective amounts for treating xerostomia ormouth dryness consist of: (a) polyvinyl pyrrolidone orvinylpyrrolidone/vinylacetate copolymer, or mixtures thereof; and (b)xanthan gum.
 4. The method of claim 1, wherein the one or more orallyacceptable carriers or excipients is selected from the group consistingof: water; one or more surfactants; and one or more buffering agents. 5.The method of claim 1, wherein the polyvinyl pyrrolidone (PVP) or aderivative thereof is vinylpyrrolidone/vinylacetate copolymer.
 6. Themethod of claim 1, wherein the composition is exclusive of anticalculusagents and abrasive polishing materials.
 7. The method of claim 1wherein the composition is in the form of a mouthwash or mouthspray. 8.The method of claim 1 wherein the PVP or derivative thereof is presentin the amount of 0.1 to 20% w/w.
 9. The method of claim 1 wherein theanionic mucoadhesive polymer is present in the range 0.02 to 20% w/w.10. The method of claim 1 wherein the weight ratio of polyvinylpyrrolidone or a derivative thereof to the anionic mucoadhesive polymeris from 5:1 to 1:1.
 11. The method of claim 1, wherein the anionicmucoadhesive polymer is xanthan gum.
 12. The method of claim 1, whereinthe polyvinyl pyrrolidone or derivative thereof is present in the amountof 0.1 to 20% by weight; and the ratio of the polyvinyl pyrrolidone orderivative thereof to the anionic mucoadhesive polymer is from 4:1 to2:1.
 13. A method of treating xerostomia or mouth dryness byadministering to a person in need thereof a liquid compositioncomprising: 0.1 to 20% by weight polyvinyl pyrrolidone or a derivativethereof; and an anionic mucoadhesive polymer; wherein the weight ratioof the polyvinyl pyrrolidone or derivative thereof to the anionicmucoadhesive polymer is from 4:1 to 2:1; wherein the liquid compositionis exclusive of abrasive polishing material.
 14. The method of claim 13,wherein the liquid composition comprises: 0.15 to 4% by weight of theanionic mucoadhesive polymer; wherein the polyvinyl pyrrolidone orderivative thereof is present in a weight percentage according to theratio of from 4:1 to 2:1 with the anionic mucoadhesive polymer.
 15. Themethod of claim 14, wherein the anionic mucoadhesive polymer is xanthangum.
 16. The method of claim 15, wherein the polyvinyl pyrrolidone orderivative thereof is polyvinylpyrrolidone,vinylpyrrolidone/vinylacetate copolymer, or mixturesthereof.
 17. The method of claim 16, wherein the polyvinyl pyrrolidone(PVP) or a derivative thereof is vinylpyrrolidone/vinylacetatecopolymer.
 18. The method of claim 17, wherein the active ingredientsfor treating mouth dryness or xerostomia in the composition consist of:vinylpyrrolidone/vinylacetate copolymer and xanthan gum.
 19. A method oftreating xerostomia or mouth dryness by administering to a person inneed thereof a liquid composition consisting of: 0.1 to 20% by weightpolyvinyl pyrrolidone or a derivative thereof; an anionic mucoadhesivepolymer; one or more orally acceptable carriers or excipients selectedfrom the group consisting of: flavoring agents, humectants, binders,sweetening agents, surfactants, preservatives, buffering agents,coloring agents and water; optionally, additional ingredients selectedfrom the group consisting of: antimicrobial agents, moisturizing agents,breath freshening agents, and desensitising agents; wherein the weightratio of the polyvinyl pyrrolidone or derivative thereof to the anionicmucoadhesive polymer is from 4:1 to 2:1.
 20. The method of claim 19,wherein the polyvinyl pyrrolidone or a derivative thereof isvinylpyrrolidone/vinylacetate copolymer and the anionic mucoadhesivepolymer is xanthan gum.